Hypothesizing mechanistic links between microbes and disease using knowledge graphs

Knowledge graphs have found broad biomedical applications, providing useful representations of complex knowledge. Although plentiful evidence exists linking the gut microbiome to disease, mechanistic understanding of those relationships remains generally elusive. Here we demonstrate the potential of knowledge graphs to hypothesize plausible mechanistic accounts of host-microbe interactions in disease. To do so, we constructed a knowledge graph of linked microbes, genes and metabolites called MGMLink. Using a semantically constrained shortest path search through the graph and a novel path prioritization methodology based on cosine similarity, we show that this knowledge supports inference of mechanistic hypotheses that explain observed relationships between microbes and disease phenotypes. We discuss specific applications of this methodology in inflammatory bowel disease and Parkinson's disease. This approach enables mechanistic hypotheses surrounding the complex interactions between gut microbes and disease to be generated in a scalable and comprehensive manner.